1 Phosphodiesterase Type IV Inhibitors

• Published in: Progress in Medicinal Chemistry Vol. 33; pp. 1 - 52
• Main Authors: Palfreyman, Malcolm N., Souness, John E.
• Format: Book Chapter
• Language: English
• Published: Elsevier Science & Technology 1996
• ISBN: 9780444823106; 0444823107
• ISSN: 0079-6468; 1875-7863
• DOI: 10.1016/S0079-6468(08)70302-3

This chapter summarizes the biochemistry, molecular biology, regulation, and pharmacology of phosphodiesterase IV (PDE IV). The structure–activity relationships (SARs) of known groups of compounds against PDE IV are discussed in detail, as are the in vitro and in vivo actions of PDE IV inhibitors, which have led to the current guarded optimism of their therapeutic potential. Finally, the side effects of these compounds, which may have an important impact on the eventual clinical utility of PDE IV inhibitors, are critically assessed. The next few months will reveal whether the current, guarded optimism in the therapeutic potential of PDE IV inhibitors will be fulfilled. Only a limited amount of information on the clinical efficacy of relatively weak PDE IV inhibitors in asthma and skin disorders (psoriasis) has been published. Several companies currently have, or will have, compounds undergoing clinical evaluation in asthma patients. Although a large body of information from acute animal studies suggests that PDE IV inhibitors will be effective in the treatment of asthma, and bronchodilating activity has been demonstrated in the clinic with weak PDE IV inhibitors and mixed PDE III/IV inhibitors, long-term studies with the newer, highly potent compounds will be required to determine whether they suppress the mucosal inflammation associated with this chronic disease. This will ultimately determine whether they will assume a position of importance in prophylactic asthma therapy.